1. Field of the Invention
The present invention relates to photocrosslinkable, biodegradable polymeric materials that in one application can be injected and then hardened in situ to form scaffolds for tissue and/or skeletal reconstruction.
2. Description of the Related Art
The clinical needs for bone regeneration are diverse, and there are roughly 1,000,000 patients who have skeletal defects each year in the United States that require bone graft procedures to achieve union. These include applications arising from resection of primary and metastatic tumors, bone loss after skeletal trauma, primary and revision total joint arthroplasty with bone deficiency, spinal arthrodesis, and trabecular voids following osteoporotic insufficiency fractures. Current clinical decision making in the selection, preparation and application of bone graft materials often involves many factors. From a structural perspective, several decisions need to be addressed prior to deciding on a surgical management plan.
First, the type of bone lost must be determined. The defect may be trabecular bone, cortical bone, or a combination of both structural bone types. Second, the nature of the defect must be defined, whether it is contained and has a bony or soft tissue shell, or is non-contained and represents a segmental loss of bone continuity. Third, the size of the defect (size of trabecular voids or length of segmental defects) must be determined. Mechanical issues that enter into the graft selection decision include the skeletal location of the defect to be reconstructed and the anticipated loads in that location. In addition, biologic issues such as host co-morbidities (for example, diabetes) may all have an effect on the bone graft incorporation process. Finally, surgical issues that play a role in the selection of graft material include consideration regarding the size of the surgical access portal relative to the size of the defect.
Current clinical methods of treating skeletal defects involve bone transplantation or the use of other materials to restore continuity. Autologous bone graft has been the gold standard of bone replacement because it provides such essential elements as osteogenic cells, osteoinductive factors, and an osteoconductive matrix for healing. However, the limited supply of autograft bone, and donor site morbidity both restrict the spectrum of cases in which it can be used alone. Allograft bone, although available in abundant supply, has drawbacks that include reduced rates of graft incorporation compared to autograft bone, and the possibility of pathogen transfer from donor to host.
Metals provide immediate mechanical support at the defect site but exhibit less than ideal overall integration with host tissue and can eventually fail due to fatigue loading if the bone does not heal prior to fatigue failure of the metal. Ceramics, such as β-tricalcium phosphate (β-TCP) and hydroxyapatite are both osteoconductive, and have found clinical use as surface coatings on metal prostheses to enhance bonding of those prostheses to bone. In particulate form, they offer increased mechanical strength to polymeric composite materials primarily in compression, but are less effective in enhancing resistance to torsional and bending forces. Poly(methyl methacrylate) bone cement can be injected or molded and is sometimes used to fill both cavitary and segmental defects, such as those that result from the curettage of a giant cell tumor or from the resection of a vertebral body in metastatic disease to the spine, respectively. However, the temperature can rise up to 100° C. during the exothermic polymerization reaction, and the heat released risks local tissue injury. Additionally, poly(methyl methacrylate) is non-biodegradable and can thus accumulate fatigue damage with time and eventually undergo mechanical failure.
Synthetic biodegradable polymers may provide treatment options not currently available. These materials can be manufactured in virtually unlimited supply and the flexibility in their design allows the synthesis of a wide range of polymers with varying mechanical, biologic, degradation, and rheologic properties. For instance, their mechanical and degradation properties can be manipulated by changing the polymer molecular weight during synthesis, and can thus be tailored to fit a particular application. The injectable nature of the skeletal regeneration biomaterial would be ideal to fill defects with limited accessibility or irregular shape. For example, minimally invasive endoscopic techniques now in clinical use would allow the injectable form of the biomaterial to be inserted for posterolateral intertransverse process spinal fusion. This would decrease the surgical trauma from the extensive exposure and muscle stripping that must now be done to put the graft material into position. The injectable material could be placed into cancellous voids from periarticular fractures, osteoporotic spinal fractures, or bone cysts without creating a large access hole in the surrounding cortical bone. These clinical situations represent the motivation for the development of injectable biodegradable polymeric composite materials for bone tissue engineering.
Thus, biodegradable scaffolds that can be injected and crosslinked in situ to fill defects offer attractive additions to existing methods (see, Yaszemski et al., “Clinical needs for bone tissue engineering technology”, in Bone Engineering, J. E. Davis, Ed. Toronto, Em Squared, 2000, pp. 541-547). Recently developed injectable materials have fulfilled many design criteria for diverse orthopedic applications. A candidate material of this type is poly(propylene fumarate) (PPF), an unsaturated linear polyester that can be modified or crosslinked through its fumarate double bonds. PPF degrades by simple hydrolysis of the ester bonds and the degradation time depends on polymer characteristics such as molecular weight, type of crosslinker, and crosslinking density. Although many efforts have been made to explore the applications of PPF-based materials, there are still many important limitations of this material. The propylene glycol in each repeating unit provides only one free rotating carbon-carbon bond that contributes to the rigidity of the PPF polymer chain. In addition, a crosslinker is needed to form crosslinked PPF networks via redox initiation, which may lead to cytotoxicity associated with unreacted crosslinking monomers.
Poly(ε-caprolactone) (PCL) is a well-known biodegradable polymer and FDA-approved for use as resorbable sutures. It has excellent biocompatibility and flexibility. PCL was recently studied as a potential material for a temporary joint spacer (Elfick, Biomaterials, 23, p. 4463-4467, 2002) and tissue-engineered skin (Ng, Tissue Engineering, 7, p. 441-455, 2001).
An injectable copolymer based on PCL and fumarate segments, poly(caprolactone fumarate) (PCLF) is described in PCT International Patent Application No. WO 2005/004811. Due to the presence of PCL unit, the PCLF chain is much more flexible than the PPF chain. This renders PCLF self-crosslinkable by redox initiation without the use of any crosslinker.
The previously developed PCLF, however, has a dark brown color due to the proton scavenger triethylamine used in the condensation reaction. Because of the dark color, UV light cannot go through the PCLF material to allow it to crosslink efficiently by photoinitiation. Photocrosslinking is the formation of a covalent linkage between two macromolecules or between two different parts of one macromolecule. Photocrosslinking allows in vivo curing, which provides great flexibility for the placement and handling of implantable polymers for surgeons. The main advantages of photocrosslinking over other crosslinking techniques are spatial and temporal control of the polymerization, fast curing rates at room temperature, and ease of fashioning and flexibility during implantation (see Anseth, Nature Biotechnology, 17, p. 156-159, 1999).
Therefore, there is a need for photocrosslinkable poly(caprolactone fumarate), and in particular there is a need for photocrosslinkable poly(caprolactone fumarate) that is useful as a biocompatible, bioresorbable, injectable, and in-situ hardening scaffold for tissue engineering applications.